The subject invention is directed generally to dispersed systems and more particularly to a method of stabilizing a taxane in a dispersed system, and to a stable taxane-containing liposome preparation.
Throughout this application various publications are referenced, many in parenthesis. Full citations for each of these publications are provided at the end of the Detailed Description. The disclosures of each of these publications in their entireties are hereby incorporated by reference in this application.
Paclitaxel (taxol, FIG. 1) is a diterpenoid natural product that is undergoing intensive evaluation as an anticancer agent (Wani et al. 1971; Donehower et al. 1987; Grem et al. 1987; Rowinsky et al. 1990). The clinical development of all taxanes, including the prototype paclitaxel, has been hampered by poor aqueous solubility (Suffness 1993; Straubinger 1995), which necessitates administration of the drug in a vehicle such as Cremophor EL mixed with ethanol. Unfortunately, the formulation vehicle causes a variety of adverse reactions, including anaphylactoid hypersensitivity reactions (Donehower et al. 1987; Lorenz et al. 1977). Newer semisynthetic taxanes in clinical use (eg. docetaxel (Taxotere)) have greater water solubility, but a potentially toxic solubilizer (polysorbate 80) nonetheless is required for administration (Bissery et al. 1991; Tomiak et al. 1992).
Previously, phospholipid-based liposome formulations for paclitaxel, Taxotere, and other active taxanes have been developed (Straubinger et al. 1993; Straubinger et al. 1994; Sharma et al. 1993; Sharma and Straubinger 1994; A. Sharma et al. 1995a), and the physical properties of these and other taxane formulations have been studied (Sharma and Straubinger 1994; U.S. Sharma et al. 1995; Balasubramanian and Straubinger 1994; Balasubramanian et al. 1994). The main utility of these formulations is the elimination of toxicity related to the Cremophor EL excipient, and a reduction in the toxicity of the taxane itself, as demonstrated in several animal tumor models (Sharma et al. 1993; A. Sharma et al. 1995; Sharma et al. 1996). This observation holds for several taxanes in addition to paclitaxel (A. Sharma et al. 1995). In some cases, the antitumor potency of the drug appears to be slightly greater for the liposome-based formulations (Sharma et al. 1993).
These formulations consist of phospholipids and other additives, in addition to the taxane, and may be stored in a dried state. Upon addition of an aqueous phase to the mixture, particles form spontaneously and may take the form of liposomes (Straubinger et al. 1993). Liposomes are closed, vesicular structures consisting of a limiting bilayer membrane surrounding an aqueous core. A preferred formulation composition (Sharma and Straubinger 1994) contains a neutral (zwitterionic) phospholipid such as lecithin (phosphatidylcholine, 80-90% by mole ratio), along with a negatively charged phospholipid such as phosphatidylglycerol (10-20%). The latter prevents aggregation of the particles through electrostatic repulsion. The most stable taxane content is in the range of 3-4 mole % (relative to total phospholipid content); such liposomes may be physically and chemically stable for 2 months after hydration. Under most conditions, paclitaxel formulations containing higher (eg. 8 mole %) drug concentrations are very unstable and may precipitate within minutes of preparation (Sharma and Straubinger 1994).
The greatest concern over these formulations has been the relatively low taxane content of acceptably stable formulations (3-5 mole %), which necessitates the administration of a large amount of phospholipid (5-10 gm) to patients in order to give the anticipated dose of drug. Although humans frequently are given large amounts of lipids intravenously for Total Parenteral Nutrition (TPN), a major developmental aim has been to produce taxane liposomes having a higher taxane content.
The subject invention addresses this need by providing a method of stabilizing a taxane in a dispersed system, which method comprises exposing the taxane to a molecule which improves physical stability of the taxane in the dispersed system. By improving physical stability of the taxane in the dispersed system, higher taxane content can be achieved. The invention thus further provides a stable taxane-containing liposome preparation comprising a liposome containing one or more taxanes present in the liposome in an amount of less than 20 mol % total taxane to liposome (preferably 9-20 mol %), wherein the liposome is suspended in a glycerol:water composition having at least 30% glycerol.